Many disorders and conditions of the central nervous system are influenced by the serotonergic neurotransmitter system. For example, serotonin (5-hydroxytryptamine; 5-HT) has been implicated in a number of disorders and conditions that originate in the central nervous system. The serotonin receptors are divided into seven main classes 5-HT1-5-HT7. Additionally, the 5-HT2 family of serotonin receptors is subdivided into the 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes. For reviews dealing with the classification and function characteristics of serotonin receptors, see for example: Hoyer, D. et al. Pharmacol. Rev. 1994, 46, 157-203; Saxena, P. R. Pharmacol. Ther. 1995, 66, 339-368; Barnes, N. M. et al. Neuropharmacol. 1999, 38, 1083-1152; Roth, B. L. et al. Pharmacol. Ther. 1998, 79, 231-257.
The 5-HT2A receptor subtype is expressed in the human brain, including many cortical, limbic, and forebrain regions and is postulated to be involved in the modulation of higher cognitive and affective functions. The 5-HT2A receptor subtype is also expressed on mature blood platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis. Several lines of evidence strongly implicate the 5-HT2A receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, schizophrenia, obsessive-compulsive disorder, sexual function disorders, sleep disorders, and eating disorders, such as anorexia nervosa. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al., Invest. Ophthalmol. Vis Sci. 1995, 36, 719 and 734, respectively). The compound (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol (also known as M-100907) has been shown to be a potent antagonist of human 5-HT2A receptors and is described in WO 91/18602.
The 5-HT2A receptor subtype has further been suggested to be involved in urological disorders such as diabetic nephropathy and urinary incontinence (diabetic nephropathy, see: Ishimura, E. et al. Nephron 1997, 76, 227-229; urinary incontinence, including coexisting diabetes, see: Kodama, M. et al. Int. J. Urol 2000, 7, 231-235 and Ichiyanagi, N. et al. J. Urol. 2002, 168, 303-307).
Compounds that have an effect on the 5-HT2A receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above.
Information Disclosure
Various classes of compounds have been disclosed to act as antagonists at the 5-HT2A receptor. For example, 4-aryl- or 4-heteroarylpiperazines such as those described in J. Med. Chem. 1991, 34, 2477, Chem. Pharm. Bull. 1987, 35, 1919-, Bioorg. Med. Chem. Lett. 1997, 7, 1635-1638, and Arch. Pharm. 1995, 328, 659-666. Other compound classes reported to act as 5-HT2A antagonists are disclosed in WO 0114332, WO 0004017, WO 0043362, WO 0107434, WO 0107435 and WO 0151469. A further class of 5-HT2A antagonists is represented by the N-aralkyl-piperidine-methanol derivatives disclosed in U.S. Pat. No. 5,169,096, encompassing M-100907 mentioned above. The class of 5-HT2A antagonists disclosed in U.S. Pat. No. 5,169,096 are claimed to be useful in the treatment of a variety of disease states such as anorexia nervosa, variant angina, Raynaud's phenomenon, coronary vasospasms, hypertension, profylactic treatment of migraine, cardiovascular diseases such as hypertension, peripheral vascular disease, thrombotic episodes, cardiopulmonary emergencies and arrythmias, and has anesthetic properties. See also U.S. Pat. No. 4,877,798 (fibromyalgia); U.S. Pat. No. 4,908,369 (insomnia); U.S. Pat. No. 5,106,855 (glaucoma); U.S. Pat. No. 6,004,980 (anxiety, Raynaud's phenomenon, cardiac arrythmia; extrapyramidal symptoms; drug abuse, anorexia, fibromyalgia); EP 337136 (treatment of extrapyramidal side effects associated with neuroleptic therapy). Psychotic illness such as schizophrenia and mania, among other indications are disclosed uses for M-100907 in U.S. Pat. No. 5,134,149. The use of M-100907 for the treatment of various developmental neurological disorders such as autism and attention deficit hyperactivity disorder is disclosed in WO 99/56750. The use of M-100907, and prodrugs thereof, for the treatment of symptoms of dementia, such as Alzheimer's disease, is disclosed in WO 01/89498. The use of M-100907 for the treatment of obsessive-compulsive disorders (OCD) is disclosed in U.S. Pat. No. 5,618,824.
Ketanserin (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione is a 5-HT2A antagonist that has been on certain markets for hypertension and is patented by Janssen in EP 13612 B. The use of ketanserin for the treatment of glaucoma is disclosed in EP 522226 (cf. Ophthalmologica 2001, 215, 419-423).
Sarpogrelate (butanedioic acid, mono[2-(dimethylamino)-1-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl]ester, MCI-9042; Anplag™), Mitsubishi, Japan, is a 5-HT2A antagonist used for the treatment of thromboembolism in Japan and is disclosed in EP 72942 B. The use of sarpogrelate for the treatment of glaucoma is disclosed by Mitsubishi in EP 695545 and by Senju Pharmaceutical in CA 2144810. Sarpogrelate is also reported to have therapeutic potential in the treatment of diabetic complications (cf. Hotta, N. et al. Clin. Drug Invest. 1999, 18, 199-207; Kobori, S. et al. Int. Congr. Ser. 2000, 1209, 283-286).
The 5-HT2A antagonist amperozide (4-(4,4-bis(4-fluorophenyl)butyl)-N-ethyl-1-piperazinecarboxamide) has been disclosed to possess antipsychotic properties and was first claimed by Pharmacia's subsidiary Ferrosan in the patent DE 02941880. Its use for the treatment of substance abuse is disclosed in the associated patent WO 09216211.
Ajinomoto is developing the 5-HT2A antagonist and platelet aggregation inhibitor, AT-1015 (N-[2-{4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino}-ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate) for the potential treatment of thrombotic conditions (cf. European Journal of Pharmacology 2001, 433(2-3), 157-162).
Senju Pharmaceuticals has disclosed a series of 1,5-benzoxa-thiepine derivatives (e.g., methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate) in U.S. Pat. No. 5,538,974 and which are stated to be serotonin S2 receptor antagonists and being useful for the treatment of glaucoma.
WO 00/64441 discloses, inter alia, a series of known 5-HT2A antagonists (e.g., M-100907) for therapeutic or prophylactic treatment of disorders involving bronchoconstriction.
Some structurally related compounds to those of formula (I) in the present invention are disclosed in J. Med. Chem. 1981, 24, 93-101 and in GB 1,440,722. Particular compounds are 3-piperazin-1-yl-1H-quinoxalin-2-one, 1-methyl-3-piperazin-1-yl-1H-quinoxalin-2-one, 3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one, and 3-(1-piperazinyl)-1-[2-(dimethylamino)-ethyl]-2(1H)-quinoxalinone. 1-Benzyl-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one is disclosed in Chem. Pharm. Bull. 1993, 41, 1832-1841. WO 00/76984 discloses pyrazinyl ether compounds that bind to the 5-HT2C receptor.